Table 2.
Novel medication treatments for anxiety disorders.
| Medication Class | Mechanism of action | FDA approvals | Past RCTs in anxiety | Ongoing/future trials in anxiety |
|---|---|---|---|---|
| Serotonergic agents: | ||||
| Vilazodone | Selective 5-HT reuptake inhibitor, 5-HT1A partial agonist (90) | MDD | GAD (90, 91) SAD (93) Sep. Anxiety (92) |
SAD (NCT01712321) |
| Vortioxetine | Selective 5-HT reuptake inhibitor 5-HT3 antagonist 5-HT1A agonist (95) | MDD | GAD (95–98) PD (99) |
Comorbid SAD, MDD (NCT04220996) |
| Gepirone ER | 5-HT1A partial agonist (102) | None | None | GAD (103) |
| Tandospirone | 5-HT1A partial agonist (104) | None | None | GAD (NCT01614041) |
| PRX-00023 | 5-HT1A partial agonist (106) | None | None | None |
| TGFK08AA | 5-HT1A partial agonist (89) | None | None | GAD (89) |
| TGW00AA | 5-HT1A partial agonist (107) | None | None | GAD, SAD (107) |
| AVN-101 | 5-HT6 receptor antagonist (108) | None | None | Anxiety Disorders (109) |
| Ondansetron | 5-HT3 receptor antagonist (110) | Nausea/vomiting | GAD (110) PD (111) |
None |
| Agomelatine | Melatonin-1/2 agonist, 5-HT2C antagonist (112) | None | GAD (113) | None |
| Psilocybin | 5-HT2A, 5-H1A, 5-HT2C agonist (118) | None | “Life-threatening anxiety” (118) | Cancer-related anxiety (NCT00957359) |
| Lysergic diethylamide (LSD) | Unclear, modulates multiple 5-HT receptors (119) | None | None | “Life threatening anxiety” (NCT03153579) |
| Glutamate: | ||||
| LY354740 | mGluR2-3 agonist (121) | None | PD (121) | None |
| LY544344 | mGluR2-3 agonist (122) | None | GAD (122) | None |
| JNJ40411813 (ADX- 71149) | mGluR2 (+) allosteric modulator (123) | None | Anxious depression (123) | None |
| Ketamine | NMDA receptor antagonist (124) | MDD | SAD (137) | None |
| Riluzole | Inhibits glutamate release (143) | Amyotrophic lateral sclerosis | GAD (143–145) | None |
| Troriluzole (BHV-4157) | Reduces synaptic glutamate (NCT03829241) | None | GAD (NCT03829241) | None |
| D-cycloserine (DCS) | NMDA partial agonist (148) | Tuberculosis | PD, SAD and specific phobias (153–167) | None |
| Memantine | NMDA receptor antagonist (169) | Alzheimer's dementia | GAD (169) | None |
| Nitrous Oxide (N2O) | NMDA receptor antagonist (170) | Inhaled anesthetic | None | None |
| GABAergic medications: | ||||
| AZD7325 | GABA-A alpha-2-3 modulator (NCT00808249) | None | GAD (NCT00808249) | None |
| PF-06372865 | GABA-A (+) allosteric modulator (176) | None | GAD (176) | None |
| BNC-210 | α7 nicotinic Ach (–) allosteric modulator, GABA modulator (177) | None | GAD (177) | None |
| SAGE-17 | GABA-A (+) allosteric modulator (180) | None | None | GAD (179) |
| Neuropeptides: | ||||
| Oxytocin | Unclear | Labor induction | SP (184) SAD (188) |
Anxiety + depression (NCT03566069) |
| LY686017 | Neurokinin-1 antagonist (194) | None | SAD (194) | None |
| L-759274 | Neurokinin-1 antagonist (195) | None | GAD (195) | None |
| Neuropeptide Y | Y1 agonist (197) | None | PTSD (199) | None |
| SSR149415 | V1b antagonist (202) | None | MDD + GAD (202) | None |
| SRX246 | V1a antagonist (203) | None | None | Experimental anxiety (NCT02922166) |
| Pexacerfont (BMS-562086) | CRF-1 antagonist (210) | None | GAD (210) | None |
| Verucerfont (GSK561679) | CRF-1 antagonist (NCT00555139) | None | GAD (NCT00555139) | None |
| Emicerfont (GW876008) | CRF-1 antagonist (NCT00555139) | None | GAD (NCT00555139) | None |
| Suvorexant | Orexin 1,2 antagonist (216) | Primary Insomnia | PD (NCT02593682) | None |
| Neurosteroids: | ||||
| Mifepristone (RU486) | Progesterone inhibitor (220) | Early pregnancy termination | PTSD, GAD, PD or anxiety NOS (220) | None |
| PH94B | Binds to nasal chemosensory receptors to trigger neural circuits (221) | None | SAD (221, 222) | Adjustment disorder with anxiety symptoms (NCT04404192) |
| Cannabinoids: | ||||
| Cannabidiol (CBD) | CB1 (–) allosteric modulator, CB2 antagonist-inverse agonist, 5HT1A agonist (229) | None | SAD (26, 225, 227) | PD, GAD, SAD agoraphobia (NCT03549819) |
| Delta-9-tetrahydrocannabinol | CB1, CB2 partial agonist (229) | None | None | None |
| Dronabinol | CB1 agonist (229) | Chemo-related nausea/vomiting | None | None |
| Nabilone | CB1, CB2 agonist (229) | Chemo-related nausea/vomiting | GAD, “anxiety neuroses” (237, 238) | None |
| Natural remedies: | ||||
| Kava | Unclear, activity on Na, Ca channels or GABA-A receptor (244) | None | GAD (247) | None |
| Galphimine-B (G-B) | Unclear, inhibition of DA neurons in ventral tegmental area (250) | None | GAD (250) | Anxiety (NCT03702803) |
| Chamomile | Unclear, modulates GABA receptors (251) | None | GAD (251) | None |
| Lavender | Inhibition of voltage-gated Ca channels (249) | None | GAD (248, 249) | Dental anxiety (NCT04285385) Pre-operative anxiety (NCT03445130) |
| Saffron | Unclear, inhibiting 5-HT reuptake in synapses (252) | None | Anxiety symptoms (252) | GAD (NCT02800733) |
Key: 5-HT, Serotonin; Ach, Acetylcholine; CB, Cannabinoid Receptor; CRF, Corticotropin Releasing Factor; ER, XR, Extended Release; FDA, Food and Drug Administration; GABA, Gamma Aminobutyric Acid; GAD, Generalized Anxiety Disorder; MDD, Major Depressive Disorder; NMDA, n-methyl-d-aspartate; NRI, Norepinephrine Reuptake Inhibitor; NOS, Not Otherwise Specified; PD, Panic Disorder; RCT, Randomized Controlled Trial; SAD, Social Anxiety Disorder; Sep. Anxiety, Separation Anxiety Disorder; SNRI, Serotonin Norepinephrine Reuptake Inhibitor; SSRI, Selective Serotonin Reuptake Inhibitor.